Benzoic acid and benzoic acid ester derivatives having antiflammatory and analgesic activity

ABSTRACT

Novel benzoic acid or benzoic acid ester derivatives, pharmaceutical compositions and methods of use thereof are the present invention. Utility is for the treatment of arthritis, asthma, Raynaud&#39;s disease, inflammatory bowel disorders, trigeminal or herpetic neuralgia, inflammatory eye disorders, psoriasis, dental pain, and headaches, particularly vascular headache, such as migraine, cluster, mixed vascular syndromes, as well as nonvascular, tension headaches.

This is a divisional of U.S. application Ser. Nos. 929,035 filed Nov.10, 1986, 929,258 filed Nov. 10, 1986 and 928,956 filed Nov. 10, 1986,which are each divisions of U.S. application Ser. No. 811,567 filed Dec.20, 1985, now U.S. Pat. No. 4,689,182 issued Aug. 25, 1987.

BACKGROUND OF THE PRESENT INVENTION

The present invention is novel compounds, which are derivatives ofbenzoic acid and benzoic acid esters--having antiinflammatory activityfor the treatment of arthritis, asthma, Raynaud's disease, inflammatorybowel disorders, trigeminal or herpetic neuralgia, inflammatory eyedisorders, psoriasis, and/or having analgesic activity for the treatmentof dental pain and headache, particularly vascular headache, such asmigraine, cluster, and mixed vascular syndromes, as well as nonvascular,tension headache. Thus, the present invention is also a pharmaceuticalcomposition comprising the novel compounds together with apharmaceutically acceptable carrier or methods of use of such compoundsfor treatment of the above noted conditions.

Among known compounds are benzoic acid derivations in which thederivative is limited to a substituent having a (naphthoxy)isobutyramidocontaining group and for which compounds an antiphlogistic activity isdisclosed. See U.S. Pat. No. 4,183,954. Additionally O. Exner, et al,discloses N-(4-carboxybenzyl)acetamide in "Quantitative Evaluation ofthe Inductive Effect," Coll. Czech. Chem. Commun. 27, 2299 (1962). Butno teaching to activity or utility for the compound is indicated byExner, et al.

Compounds related to capsaicin are disclosed in a series of patents. Thecompounds are thus not benzoic acid derivatives but have various amido,sulfonylamido or amidosulfonyl and thioamido linkages in combinationwith a benzyl or a benzyl analog moiety. Such compounds are found inU.S. Pat. No. 4,313,958, that claims the use of capsaicin; U.S. Pat.Nos. 4,460,602; 4,401,663; European patent application No. 0,132,113;U.S. Pat. Nos. 4,424,203; European patent application No. 0,132,114;0,132,346 and 0,132,115 as well as European patent application Nos.0,149,544 and 0,149,545. Of these European patent application Nos.0,132,115; 0,132,346; 0,132,114; 0,132,115, 0,149,544 and 0,149,545include a short chain acyl group on the benzyl moiety. U.S. Pat. No.3,992,540 discloses 3-quinoline-carboxamides. Analgesia is disclosed asan activity for the compounds of the references. However, none of thereferences teach the compounds having the moieties such as benzoic acidmoities and their substituents, or particularly the combination ofmoieties, of the present invention.

DETAILED DESCRIPTION OF INVENTION

The novel compounds of the present invention have the followingstructural formula: ##STR1## wherein: (a) R₁ is tetrazolyl or COOR'wherein R' is H or lower alkyl of 1 to 4 carbons, inclusive;

(b) B is ##STR2## (c) X and Y are independently H or lower alkyl of 1 to4 carbons, inclusive;

(d) R₂ is alkylene, alkenylene, alkynylene branched or linear chains of1 to 11 carbons, inclusive;

(e) Q is CH₃, COOH, Br, NH₂, H, imidazolyl, cyclohexyl, ##STR3## andnontoxic, pharmaceutically acceptable base or acid addition saltsthereof, with the proviso that when B is (B₁) and Q is H, then R₂ is notmethylene.

The term "lower alkyl of 1 to 4 carbons" means a straight or branchedhydrocarbon chain up to 4 carbon atoms such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, secondary butyl or tertiary butyl.

The terms alkylene, alkenylene and alkynylene are divalent hydrocarbonstraight or branched chains containing one or more single, double ortriple carbon to carbon bonds, respectively.

Preferred embodiments of the present invention contain COOH as shown inthe following formula (II): ##STR4## wherein X, Y, B, R₂ and Q are allas defined above. More preferred embodiments of the present inventionare compounds of formula II wherein B is B₁ and X, Y, R₂ and Q are asdefined above. The most preferred embodiment of the present invention isthe compound N-(4-carboxybenzyl)nonanamide. The preferred method of useis for treating headaches, particularly migraines.

Examples of suitable acids for the preparation of the acid additionsalts are inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, and the like, and organic acids such asacetic acid, benzoic acid, tartaric acid, fumaric acid, succinic acid,maleic acid, arginine acid, lactic acid, tartaric acid, and sulfonicacids such as methansulfonic acid, ethansulfonic acid, benzenesulfonicacid or p-toluenesulfonic acid.

The base salts of the present inventions include those safe for topicalor systemic administration, such as sodium, potassium, calcium,magnesium, and ammonium salts or the like.

Generally, the preparation of the compounds of the present invention isrepresented by the following scheme: ##STR5## wherein R₁, X, Y, B, R₂ Qare as defined above and Hal is chloro, bromo, or iodo, but preferablychloro.

The preparation uses standard synthetic techniques used in the examplesor analogous to those used in the examples hereinafter. The startingmaterials for the preparation are readily available, known or can beprepared by known methods.

The compositions containing the compounds of the formula (I') ##STR6##wherein: (a) R₁ is tetrazolyl or COOR' wherein R' is H or lower alkyl of1 to 4 carbons, inclusive;

(b) B is ##STR7## (c) X and Y are independently H or lower alkyl of 1 to4 carbons, inclusive;

(d) R₂ is alkylene, alkenylene, alkynylene branched or linear chains of1 to 11 carbons, inclusive;

(e) Q is CH₃, COOH, Br, NH₂, H, imidazolyl, cyclohexyl, ##STR8## andnontoxic, pharmaceutically acceptable base or acid addition saltsthereof, are comprised of an analgesic or antiinflammatory effectiveamount of a compound of formula I' as defined above or theirpharmaceutically acceptable base or acid addition salts and apharmaceutically acceptable carrier. Such compositions may be one of abroad range of known forms for topical or systemic administration.

The methods of use are for the treatment in mammals, particularly inhumans, of various conditions such as enumerated above either fordiseases known as inflammatory or for pain. An ordinarily skilledphysician would recognize such conditions. The compounds of formula Iare active in animal tests which are generally recognized as predictivefor antiinflammatory or analgesic activity. Regardless of the route ofadministrations elected, the compounds of the present invention areformulated into pharmaceutically acceptable dosage forms by conventionalmethods known to the pharmaceutical art. In general a preferred methodof administration is, however, by oral dosage forms.

The compounds can be administered in such unit oral dosage forms astablets, capsules, pills, powders, or granules. They may also beadministred rectally or vaginally in such forms as suppositories orbougies. They may also be introducd parenterally, (e.g., subcataneously,intravenously, or intramuscularly), using forms known to thepharmaceutical art.

An effective but nontoxic amount of the compound of formula I or thesalts thereof is employed in treatment. The dosage regimen for treatinginflammation or pain by the compounds of formula I and their salts asdescribed above is selected in accordance with a variety of factorsincluding the type, age, weight, sex, and medical condition of thesubject, the severity of the inflammation or pain, the route ofadministration and the particular compound employed. Determination ofthe proper dosage for a particular situation is within the skill of theart. Generally, treatment is initiated with smaller dosages which areless than the optimum dose of the compound. Thereafter the dosage isincreased by small increments until the optimum effect under thecircumstances is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day if desired.

Initial dosages of the compounds of the invention are ordinarily in thearea of 1 mg/kg up to at least 100 mg/kg per dose orally, preferably 30to 100 mg/kg orally are given. Each dose is given from one to four timesdaily or as needed. When other forms of administration are employedequivalent doses are administered.

An illustrative example of the activity for use as described above forthe novel compounds of the present invention is an ED₅₀ of 33.03 mg/kgfor the compound of Example 1 described in the following material whenadministered in a test based on that of Koster et al. [Fed. Proc., Vol.18 (1959), p. 412] in which the peritoneal injection of acetic acid tomice provokes repeated stretching and twisting movements which persistfor more than 6 hrs. Analgesics prevent or surpress these syndromeswhich are considered to be an exteriorization of a diffuse abdominalpain. A 1% solution of acetic acid in water is used at a dose of 0.01ml/g or 100 mg/kg of acetic acid to release the syndrome.

The Example 1 compound is subcutaneously administered 30 minutes beforethe acetic acid injection and the mice are fasted 24 hrs before thestart of the test. The stretching for the mice is observed and totaledfor each mouse in a 15 minute observation period starting just after theacetic acid injection. The results are expressed as mg/kg which amountproduces the desired inhibition of stretching or "writhing" in 50percent of a population.

Additionally, the same Example 1 compound was effective at a dose of 100mg/kg administered i.p. in reducing the inflammatory response to aninjection of carrageenan into the rat foot pad. This is a commonlyemployed standard assay for the identification of antiinflammatoryactivity, based on the method described by Winter et al. (Proc. Soc.Exptl. Biol. N.Y. vol 111 (1962), p. 544).

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following Examples will further illustrate the invention, withoutlimiting it thereto.

EXAMPLES EXAMPLE 1

N-(4-Carboxybenzyl)nonanamide

Methyl 4-(aminomethyl)benzoate hydrochloride (6.0 g, 0.03 moles) istreated with 50 mL 1N N_(a) OH and the mixture extracted with ether(3×50 mL). The combined ether extracts are dried with anhydrouspotassium carbonate and evaporated to leave the amine base as a whitesolid. This residue is dissolved in 100 mL methylene chloride, to whichis added 2.85 g pyridine. Nonanoyl chloride (6.36 g, 0.036 moles) in 10mL methylene chloride is then added dropwise to the mixture withstirring over a 5 min period. The thick pasty mass which formed after afew minutes is stirred at room temperature for 45 min, at which time 30mL saturated sodium bicarbonate is carefully added. The mixture isstirred vigorously for 15 min, after which the layers are separated andthe organic layer extracted with 2N HCl (30 mL), and dried overanhydrous sodium sulfate. Evaporation of the solvent leaves a waxyresidue which is crystallized from isopropyl ether as colorless plates,m.p. 94.5°-95.5° C.

The crystalline product (2.0 g) is dissolved in tetrahydrofuran (30 mL)to which is added 1N N_(a) OH (10 mL). The heterogeneous mixture isstirred overnight at room temperature. The resulting clear solution ismade acidic by addition of 2N HCl, and the mixture partitioned betweenchloroform (250 mL) and water 200 mL). The chloroform layer is driedover sodium sulfate and evaporated to leave a waxy residue, which iscrystallized as colorless needles from methanol/water. A yield of 1.36g, of the desired product N-(4-carboxybenzyl)nonamide is obtained. M.p.178°-179.5° C.

In a procedure analogous to that described in Example 1 above but usingthe appropriate acid chloride the following compounds are prepared.

EXAMPLE 2

N-(4-Carboxybenzyl)decanamide sodium salt, m.p. 250° C.

EXAMPLE 3

N-(4-Carboxybenzyl)heptanamide, m.p. 179°-180° C.

EXAMPLE 4

N-(4-Carboxybenzyl)octanamide, m.p. 180° C.

EXAMPLE 5

N-(4-Carboxybenzyl)phenylacetamide, m.p. 220°-221° C.

EXAMPLE 6

N-(4-Carboxybenzyl)-4-hydroxy-3-methoxycinnamamide, m.p. 233°-234° C.

EXAMPLE 7

N-(4-Carboxybenzyl)-4-phenylbutyramide

4-(Aminomethyl)benzoic acid (3.6 g) is suspended in methylene chloride(100 mL), to which 15 mL triethylamine is added. Chlorotrimethylsilane(10 mL) is then added and the mixture allowed to stir at roomtemperature for 1 hr. The mixture is then cooled in an ice bath and4-phenylbutyryl chloride (5.3 g) in methylene chloride (10 mL) is addeddropwise and the resulting mixture stirred for 30 min at 0° C., followedby an additional 3 hrs at ambient temperature. The mixture is treatedwith 75 mL 1N HCl, after which the organic layer is separated andextracted with 1N HCl. The precipitate which had formed is recovered byfiltration and recrystallized two times from methanol/l N HCl to givepure N-(4-carboxybenzyl)-4-phenylbutyramide. M.p. 178°-179° C.

A procedure analogous to that described in Example 7 using theappropriate starting material produces the following compound:

EXAMPLE 8

N-(4-Carboxybenzyl)undecanamide, m.p. 179°-180° C.

EXAMPLE 9

N-(4-Carboxybenzyl)-(2-naphthoxy)acetamide

(2-Naphthoxy)acetic acid (8.5 g) is suspended in 160 mL methylenechloride and treated with 1,1'-carbonyldiimidazole (6.8 g) which isadded in small portions. After stirring for 3 hrs at room temperatureunder a nitrogen atmosphere, the mixture is added dropwise to apreviously prepared solution of alphaamino-p-toluic acid (1.4 g),chlorotrimethylsilane (10 mL), and triethylamine (11 mL) in 250 mLmethylene chloride at 0° C. The final mixture is stirred at roomtemperature under a nitrogen atmosphere overnight. The mixture iscombined with 200 mL 1N HCl and shaken, after which the resultantprecipitate is collected by suction filtration. The precipitate isrecrystallized from methanol/2N HCl, m.p. 188°-189° C. asN-(4-carboxybenzyl)-(2-naphthoxy)acetamide.

EXAMPLE 10

N-(4-Carboxybenzyl)cinnamamide

1,1'-Carbonyldiimidazole (3.71 g) is added to an ice-cold stirredsolution of cinnamic acid (3.13 g) in 30 mL tetrahydrofuran. Afterstirring for an additional 1 hr, methyl 4-(aminomethyl)benzoatehydrochloride (4.7 g) and triethylamine (3.23 mL) are added and thefinal mixture stirred while immersed in an ice water bath for anadditional 30 min, followed by stirring overnight at room temperature.After removal of the solvent by rotary evaporation, the residue is takenup in chloroform (250 mL) and extracted with water (200 mL), 1N HCl(3×50 mL), water 100 mL), saturated sodium bicarbonate (100 mL), brine(100 mL) and the final chloroform layer dried over anhydrous magnesiumsulfate. After evaporation of the solvent in vacuo, the crude product(2.74 g) is suspended in 100 mL tetrahydrofuran and 20 mL 2N N_(a) OHand the mixture stirred at room temperature overnight. The mixture isthen made acidic by addition of excess 1N HCl, and the precipitaterecovered by filtration. After washing the filter cake with water andpressing to remove as much water as possible, the white solid iscrystallized from methanol/2N HCl as N-(4-carboxybenzyl)cinnamamide,m.p. 238°-239° C.

A procedure analogous to that described in Example 10 using anappropriate starting material produces the following compound:

EXAMPLE 11

N-(4-Carboxybenzyl)cyclohexylacetamide, m.p. 223°-224° C.

EXAMPLE 12

N-(4-Carboxybenzyl)butyramide

4-(Aminomethyl)benzoic acid (3.0 g) is suspended in pyridine (15 mL) andthe mixture cooled in an ice water bath. Butyric anhydride (9.2 mL) isadded dropwise to the stirred suspension over a 20 min period. The icebath is removed and the mixture stirred at room temperature overnight.The mixture is poured into 150 mL ice water and made acidic (pH 1.5) byaddition of concentrated HCl. The precipitate is recovered by suctionfiltration and recrystallized from ethyl acetate to produceN-(4-carboxybenzyl)butyramide, m.p. 186.5°-187.5° C.

EXAMPLE 13

N-(4-Carboxybenzyl)hexanamide

Hexanoic acid (3.06 g) in 20 mL acetonitrile is treated withN-methylmorpholine (2.9 mL) and the mixture cooled to -20° C. withstirring. Ethyl chloroformate (2.8 mL) is then added dropwise, keepingthe temperature below or at -20° C. After stirring for an additional 40min at that temperature, the solution is transferred to a cooled (-15°C.) solution of alphaamino-p-toluic acid (2.0 g), triethylamine (15 mL),a chlorotrimethylsilane (5.0 mL) in methylene chloride (60 mL; preparedas described in Example 7). After the addition is complete, the mixtureis stirred at 5° C. for 4 hrs, followed by overnight stirring at roomtemperature. After removal of the solvents by evaporation, the residueis redissolved in methylene chloride (100 mL) and extracted with 1N HCl(2×50 mL) and brine (2×50 mL). The organic layer is dried over magnesiumsulfate and evaporated, leaving N-(4-carboxybenzyl)hexanamide as anoff-white solid. The N-(4-carboxybenzyl)hexanamide product iscrystallized from methanol/2N HCl, m.p. 178°-179° C.

EXAMPLE 14

N-1-(1-(4-Carboxyphenyl)ethyl)nonanamide

Step 1 4-(1-aminoethyl)benzoic acid

4-Acetylbenzoic acid (4.1 g) is dissolved in 50 mL ammonia-saturatedmethanol. Raney nickel catalyst (1.5 g; activity grade III) is thenadded and the mixture reduced under hydrogen atmosphere (4750 psi) at80° C. for 17 hrs. After removal of the catalyst by suction filtration,the filtrate is evaporated and the residue dissolved in H₂ O. Thesolution is passed through a 2.5×15 cm column of Dowex 50X8-400 resin(H⁺ form) and eluted with 1N NH₄ OH. Evaporation of the eluate leaves aresidue (2.9 g) which is recrystallized from H₂ O/acetone andcharacterized as 4-(1-aminoethyl)benzoic acid, m.p.>300° C.

Step 2 N-1-(1-(4-Carboxyphenyl)ethyl)nonanamide

The 4-(1-aminoethyl)benzoic acid as prepared above in Step 1 (1.5 g) issuspended in 30 mL methylene chloride containing 2.13 g pyridine andcooled to 0° C. Nonanoyl chloride (1.7 g) is dissolved in 5 mL methylenechloride and added dropwise with stirring to the cooled solution. Afterallowing the mixture to warm to room temperature, the mixture is allowedto stir an additional 2 hrs. Treatment with 1N HCl (40 mL) produces asolid residue at the interface of the two liquid phases, which isrecovered by filtration and recrystallized from methanol/water asN-1-(1-(4-carboxyphenyl)ethyl)nonanamide, m.p. 178°-180° C.

EXAMPLE 15

N-(4-carboxybenzyl)-N-methylnonanamide

Step 1 4-(methylaminomethyl)benzoic acid hydrochloride

4-Carboxybenzaldehyde (10 g) is dissolved in 50 mL aqueous methylamine(30%). Raney nickel (5 g) is added and the mixture treated with hydrogenat 1500 psi and 100° C. for 17 hrs. Removal of the catalyst by suctionfiltration and evaporation of the filtrate left a solid residue, whichis redissolved in 2N HCl (50 mL). The solution is extracted with ethylacetate (50 mL) and chloroform (50 mL) and the resultant aqueous layerevaporated to dryness. The residue is vacuum dried at 60° C. for 4 hrsand recrystallized from methanol/ethyl acetate to yield 7.65 g4-(methylaminomethyl) benzoic acid hydrochloride, m.p. 255°-261° C.

Step 2 N-(4-Carboxybenzyl-N-methylnonamide)

The 4-(methylaminomethyl)benzoic acid hydrochloride prepared in Step 1above (2.0 g) is suspended in 5 mL pyridine and cooled in ice water.Nonanoyl chloride (1.8 g) is added dropwise with stirring, and the finalsolution allowed to stir at room temperature for 18 hrs. The clearsolution is treated with 2N HCl (15 mL), and partitioned betweenchloroform and water (50 mL each). The aqueous layer is again extractedwith chloroform (25 mL) and the combined organic layers dried (Na₂ SO₄)and evaporated to leave a clear viscous oil which solidifies onstanding. The solid is crystallized from ethyl acetate/hexanes asN-(4-carboxybenzyl)-Nmethylnonanamide, m.p. 79.5°-81° C.

EXAMPLE 16

N-((4-(1H-Tetrazol-5-yl)phenyl)methyl)nonanamide

To a solution of 4-(aminomethyl)benzonitrile (5.0 g, 0.038 moles) in 100mL chloroform is added 3.82 g (0.038 moles) triethylamine. A solution ofnonanoyl chloride (6.68 g, 0.038 moles) in 10 mL chloroform is thenadded dropwise with stirring over a 10 min period and the final mixturestirred at room temperature for 18 hrs. The mixture is extracted withwater (100 mL), saturated NaHCO₃ (50 mL), 2N HCl (50 mL), dried over Na₂SO₄ and evaporated to leave 10.2 g crude N-(4-cyanobenzyl)nonanamide.This crude product is taken up in 50 mL dimethylformamide, to which isadded 2.47 g (0.038 moles) sodium azide and 2.03 g (0.038 moles)ammonium chloride. The final mixture is heated at 90°-110° C. for 4 hrsafter cooling, the mixture is diluted with water (350 mL) and theresultant precipitate recovered by suction filtration, washed withwater, and vacuum dried. Recrystallization from ethyl acetate leftN-[[4-(1H-tetrazol-5-yl)phenyl]methyl]nonanamide (2.6 g), m.p. 185°-187°C.

We claim:
 1. A method for treating pain in mammals suffering therefrom which comprises administering to such mammal an analgesic effective amount of a pharmaceutical composition comprising an effective amount of a compound of the formula: ##STR9## wherein: (a) R₁ is tetrazolyl or COOR' wherein R' is H or lower alkyl of one to four carbons, inclusive;(b) B is ##STR10## (c) X and Y are independently H or lower alkyl of one to four carbons, inclusive; (d) R₂ is alkylene, alkenylene, alkynylene branched or linear chains of 1 to 11 carbons, inclusive; (e) Q is CH₃, COOH, Br, NH₂, H, imidazolyl, cyclohexyl, ##STR11## or nontoxic, with the proviso that R₁ cannot be COOR' when B is ##STR12## (B₁) except when Q is imidazolyl; pharmaceutically acceptable acid addition or base salt thereof; and a pharmaceutically acceptable carrier.
 2. A method for reducing inflammation in mammals suffering therefrom which comprises administering to such mammal an effective amount of a pharmaceutical composition comprising an effective amount of a compound of the formula: ##STR13## wherein: (a) R₁ is tetrazolyl or COOR' wherein R' is H or lower alkyl of one to four carbons, inclusive;(b) B is ##STR14## (c) X and Y are independently H or lower alkyl of one to four carbons, inclusive; (d) R₂ is alkylene, alkenylene, alkynylene branched or linear chains of 1 to 11 carbons, inclusive; (e) Q is CH₃, COOH, Br, NH₂, H, imidazolyl, cyclohexyl, ##STR15## or nontoxic, with the proviso that R₁ cannot be COOR' when B is ##STR16## (B₁) except when Q is imidazolyl; pharmaceutically aceptable acid addition or base salt thereof; and a pharmaceutically acceptable carrier.
 3. A method for treating headaches in mammals suffering therefrom which comprises administering to such mammal an antiheadache effective amount of a pharmaceutical composition comprising an effective amount of a compound of the formula: ##STR17## wherein: (a) R₁ is tetrazolyl or COOR' wherein R' is H or lower alkyl of one to four carbons, inclusive;(b) B is ##STR18## (c) X and Y are independently H or lower alkyl of one to four carbons, inclusive; (d) R₂ is alkylene, alkenylene, alkynylene branched or linear chains of 1 to 11 carbons, inclusive; (e) Q is CH₃, COOH, Br, NH₂, H, imidazolyl, cyclohexyl, ##STR19## or nontoxic, with the proviso that R₁ cannot be COOR' when B is ##STR20## (B₁) except when Q is imidazolyl; pharmaceutically acceptable acid addition or base salt thereof; and a pharmaceutically acceptable carrier. 